Probucol is a compound having the chemical name 4,4′-(isopropylidenedithio)bis(2,6-di-t-butylphenol). Main functions of probucol are said to promote catabolism of cholesterol and its excretion into bile. Furthermore, probucol raises the catabolism rate of low-density lipoprotein (LDL)-cholesterol and reduces the serum total cholesterol level. Consequently, probucol is widely used as an agent for improving lipid metabolism in hyperlipidemia patients (including familial hypercholesterolemia and xanthoma patients).
However, probucol also has a clinically disadvantageous effect, i.e., reduces the cholesterol level in the HDL fraction (hereinafter sometimes referred to as “HDL-cholesterol”), unlike other lipid-lowering agents which have the reaction properties in LDL such as statins or fibrates (for example, refer to Non-Patent Documents 1 and 2). As the statin lipid-lowering agents, pravastatin and simvastatin known as HMG-CoA reductase inhibitors are known. As the fibrate lipid-lowering agents, fenofibrate and bezafibrate are known. It is thought that this reduction in HDL-cholesterol is due to functional inhibition of ABCA1 (for example, refer to Non-Patent Documents 3, 4, and 5).
It is known that probucol spiroquinone, probucol diphenoquinone, and probucol bisphenol according to the present invention are produced as metabolites when probucol is orally administered to a mammal (for example, prefer to Non-Patent Document 6).
Some pharmacological activities of probucol spiroquinone, probucol diphenoquinone, and probucol bisphenol (hereinafter sometimes preferred to as “bisphenol-type compounds”, or collectively the “bisphenol-type compound”) are known at present. For example, it is disclosed that probucol bisphenol has antioxidant properties and is used in combination with probucol as a lipoprotein oxidation inhibitor (for example, refer to Patent Document 1). In addition, it is known that the bisphenol-type compounds incorporate cholesterol into cells (for example, refer to Non-Patent Document 7). However, in these prior findings, functions of the bisphenol-type compounds on ABCA1 and HDL are not disclosed at all.
HDL is a lipid/protein complex particle produced by the action of helix-like apolipoproteins such as apoprotein A-I (hereinafter sometimes referred to as “apoAI”) mainly synthesized in and secreted from liver cells and small-intestine epithelial cells and the ABCA1 protein present in cell membranes. Immediately after secretion, HDL is formed as a discoidal particle composed of major constituents, apoAI and phospholipid, and called nascent HDL. This nascent HDL receives, in blood, free cholesterol from cell membranes of peripheral cells or surfaces of other lipoproteins, and forms mature spherical HDL while holding, at its hydrophobic center, cholesterol ester converted from the cholesterol by the action of LCAT (lecithin cholesterol acyltransferase).
In the above-mentioned process, HDL plays a major role in extremely important physiological function in terms of lipid metabolism called “cholesterol reverse-transport system” which takes, in blood, excessive cholesterol out of peripheral tissues and transports it to the liver. The cholesterol reverse-transport system is considered to work for removing cholesterol accumulated in blood vessel wall cells and to cause a prophylactic action on arteriosclerosis.
With respect to a relationship between blood levels of HDL cholesterol and arteriosclerosis, many epidemiological studies have been conducted. As a result, it has been recently revealed a fact that lower HDL cholesterol levels result in a higher incidence of arteriosclerosis. The improvement of low HDL-cholesterolemia is a more important and novel technology as prophylactic/therapeutic treatment of arteriosclerosis, compared to a therapy using the statins or fibrates widely used at present for reducing LDL.
At present, the blood level of HDL is determined by referring to the level of HDL-cholesterol. In general, when the blood HDL cholesterol level of a subject is lower than 40 mg/dl, the subject is diagnosed as “low-HDL cholesterolemia”.
Low-HDL cholesterolemia is found as a risk factor at a high incidence in not only arteriosclerosis but also in various disorders such as hyperlipidemia, myocardial infarction, cerebral infarction, cerebral apoplexy, obesity, diabetes mellitus, and nerve disorders caused by diabetes mellitus. Low-HDL cholesterolemia is also caused by various genetic diseases including Tangier disease. However, a useful prophylactic/therapeutic agent that acts on HDL itself has been desired to be developed. Such a prophylactic/therapeutic agent for treatment of low-HDL cholesterolemia has not been found yet.
In order to treat low-HDL cholesterolemia, a number of trials for increasing HDL have been conducted. As a result of such trials, pharmacological effects of ABCA1 have been identified.
ABCA1 is a protein mainly present in cell membranes of various organs such as the liver, small intestine, placenta, and adrenal gland, and belongs to the ABC protein family that is considered to be involved in membrane transport of various substances such as lipids, amino acids, vitamins, and saccharides (for example, refer to Non-Patent Document 8).
A recent finding revealed that ABCA1 was a protein indispensable for a reaction generating HDL from lipids in cells and a rate-limiting factor of HDL production. In addition, it was revealed that the HDL formation by ABCA1 is a main removing pathway of cellular cholesterol.
For example, in patients with Tangier disease whose ABCA1 gene has a mutation and who are deficient in expressing ABCA1, plasma HDL almost disappears (for example, refer to Non-Patent Documents 9, 10, and 11). In addition, it was found that incorporation of ABCA1 gene accelerates a HDL-generating reaction (for example, referred to Non-Patent Documents 12 and 13). Several trials are now in progress to elevate or regulate HDL cholesterol levels by increasing the ABCA1 expression level in vivo with genetic engineering technology.
For example, for increasing cholesterol efflux and HDL levels, the expression level and activity of ABCA1 are elevated by direct gene transfer of an ABCA1-coding gene into a host cell (for example, refer to Patent Documents 2 and 3). The expression and activity of ABCA1 are increased by using a certain substance to facilitate the transcription and translation of the ABCA1 gene for controlling the levels of HDL cholesterol and triglyceride (for example, refer to Patent Document 4). Furthermore, for controlling the cholesterol efflux to the outside of cells, the expression of ABCA1 is increased by activating peroxisome proliferator activated receptor-α (PPAR-α) or peroxisome proliferator activated receptor-δ (PPAR-δ) having various activities as an intranuclear receptor (for example, refer to Patent Document 5).
However, in the above-mentioned known technologies focused on ABCA1 and HDL, a genetic engineering technology or a method for activating an intranuclear receptor is used. Therefore, there are disadvantages such that the technology for a genetic therapy is immature and that a risk of unexpected side effects caused by activating an unknown gene is not ignorable. Thus, the use as a drug has not been accomplished yet.    [Patent Document 1] International Publication WO 02/04031    [Patent Document 2] International Publication WO 00/78971    [Patent Document 3] International Publication WO 00/78972    [Patent Document 4] International Publication WO 01/15676    [Patent Document 5] Japanese Unexamined Patent Application Publication No. 2003-12551    [Non-Patent Document 1] CIRCULATION, (US), 79, 1989, 16-28    [Non-Patent Document 2] JOURNAL of CARDIOVASCULAR PHARMACOLOGY, (US), 30, 1997, 784-789    [Non-Patent Document 3] BIOCHEMISTRY, (US), 35(40), 1996, 13011-13020    [Non-Patent Document 4] BIOCHIMICA et BIOPHYSICA ACTA, (Netherlands), 1483, 2000, 199-213    [Non-Patent Document 5] Arteriosclerosis, thrombosis, and vascular biology, (US), 21, 2001, 394-400    [Non-Patent Document 6] ANALYTICAL CHEMISTRY SYMPOSIA SERIES, (US), 7, 1981, 35-38    [Non-Patent Document 7] LIPIDS, (US), 29(12), 1994, 819-823    [Non-Patent Document 8] ANNUAL REVIEW of CELL BIOLOGY, (US), 8, 1992, 67-113    [Non-Patent Document 9] NATURE GENETICS, (US), 22, 1999, 336-345    [Non-Patent Document 10] NATURE GENETICS, (US), 22, 1999, 347-351    [Non-Patent Document 11] NATURE GENETICS, (US), 22, 1999, 352-355    [Non-Patent Document 12] THE JOURNAL of CLINICAL INVESTIGATION, (US), 104, 1999, R25-R31    [Non-Patent Document 13] THE FASEB JOURNAL, (US), 15, 2001, 1555-1561